Sepsis continues to cause significant morbidity and mortality and there is an unmet medical need to improve the care of septic patients. Previous treatments have failed due to a lack of understanding of the basic immune response. While sepsis has a high mortality, there is a wide range in the pathophysiologic response to pathogens. Last year we published a novel observation that provides significant insight into the heterogeneity of the septic response using the murine model of sepsis induced by cecal ligation and puncture (CLP). Several days pior to the induction of sepsis there is a pre-existing factor within the plasma that significantly increases sepsis mortality. This factor functions by decreasing the clearance of bacteria from the septic host. Preliminary data suggest that this plasma factor is an inhibitory immunoglobulin G, iIgG. This application will test the hypothesis that mice which die from sepsis have a pre-existing inhibitory IgG which reduces phagocyte function, resulting in decreased bacterial killing and decreased survival after sepsis. The first specific aim will determine the nature of the molecule and verify that it is an IgG. Additional experiments will define what portion of the antibody is responsible for the decreased bacterial killing. Most studies examining antibodies test the Fab binding to bacterial epitopes. This aim examines the role of the Fc portion of the IgG in mediating the reduced bacterial killing. Previous cancer studies have shown that antibodies which clear cancer cells both recognize the cancer cells and bind to the appropriate Fc? receptors. The second specific aim will examine the mechanisms of how this inhibitory factor decreases killing of bacteria by phagocytic cells by focusing on the Fc? receptors and bacterial killing pathways. Successful completion of this grant will help to identify a potential new pathway that alters the response to sepsis. Specifically, an important element for survival from the septic insult may be determined by humoral factors present even before the onset of sepsis. Therapeutic interventions may involve a combination of blocking the inhibitory IgG and augmenting recruitment of new phagocytic cells to allow better eradication of the bacteria.